The present invention relates to new dihydropyridine derivatives, and the use of the dihydropyridine derivatives as medicines. It is said that the activation of N-type calcium channel is concerned with diseases such as encephalopathies caused by the ischemia in the acute phase after the onset of cerebral infarction, cerebral hemorrhage (including subarachnoidal bleeding) or the like; progressive neurodegenerative diseases, e.g. Alzheimer's disease; AIDS related dementia; Parkinson's disease; dementia caused by cerebrovascular disorders and ALS; neuropathy caused by head injury; various pains, e.g. sharp pain caused by spinal injury, diabetes or thromboangitis obliterans; pain after an operation; migraine and visceral pain; various diseases caused by psychogenic stress, e.g. bronchial asthma; unstable angina and hypersensitive colon inflammation; emotional disorder; and drug addiction withdrawal symptoms, e.g. ethanol addiction withdrawal symptoms. The compounds of the present invention are effective in inhibiting the activation of N-type calcium channel and, therefore, they are usable as remedies for the above-described diseases.
The calcium channels are now classified into subtypes L, N, P, Q, R and T. Each of the subtypes is distributed specifically to organs. Particularly, it is known that N-type calcium channel is widely distributed in the central nerves, peripheral nerves and adrenal medulla cells and that this calcium channel is concerned with the death of neurons, control of blood catecholamine dynamics and control of senses such as perceptivity.
It was confirmed that peptides, omega conotoxin GVIA and omega conotoxin MVIIA which selectively inhibit the function of N-type calcium channel inhibit the release of excitatory neurotransmitter from a brain slice sample. It was confirmed by animal experiments that they prevent the advancement of neuron necrosis in a cerebrovascular disorder. It is generally considered that a compound having a clinical effect of inhibiting the function of N-type calcium channel is effective in curing encephalopathies caused by the ischemia in the acute phase after the onset of cerebral infarction, cerebral hemorrhage (including subarachnoidal bleeding) or the like; progressive neurodegenerative diseases, e.g. Alzheimer's disease; AIDS related dementia; Parkinson's disease; dementia caused by cerebrovascular disorders and ALS; neuropathy caused by head injury. In addition, it was also confirmed by animal experiments that omega conotoxin MVIIA gets rid of formalin-caused sharp pain, hot plate pain, sharp pain caused by peripheral neuropathy, etc. Therefore, this medicine is considered to be clinically effective for relieving various pains such as sharp pain caused by spinal injury, diabetes or thromboangitis obliterans; pain after an operation; migraine; and visceral pain. Further, omega conotoxin GVIA inhibits the release of catecholamine from cultured sympathetic ganglion cells, the constriction reaction of an isolated blood vessel by the electric stimulation of governing nerves, and the acceleration of catecholamine secretion from dog adrenal medulla, etc. Therefore, it is considered that compounds having the N-type calcium channel-inhibiting activity are clinically effective in treating various diseases caused by psychogenic stress, e.g. bronchial asthma, unstable angina and hypersensitive colon inflammation [Neuropharmacol., 32, 1141(1993)].
Although several peptide compounds and non-peptide compounds which selectively react on the N-type calcium channel have been disclosed hitherto (for example, WO 9313128), they are not yet used as practical medicines. Some of known compounds which react on the N-type calcium channel also react on other calcium channels than the N-type calcium channel [British Journal of Pharmacology, 122 (1), 37–42, 1997]. For example, compounds which are also antagonistic to L-type calcium channel, which deeply concern with the hypotensive effect, were incompatible with diseases for which N-type antagonists are efficacious (such as cerebral stroke, and pain caused of neuralgia, terminal cancer and spinal injury or the like).